Cardiac arrest affects an estimated 500,000 Americans annually, and fewer than 25% patients will survive to discharge due in large part to overwhelming CNS injury. The post-resuscitation syndrome following cardiac arrest (PCAS) encompasses the damaging effects of tissue ischemia and the delayed effects of ischemic reperfusion injury (IRI). Activation of the innate immune response is a prime mediator of the delayed microvascular damage, increased vascular permeability and progressive tissue damage observed after resuscitation. In particular, blocking leukocyte recruitment to the CNS significantly reduces the extent of brain injury observed after ischemic challenge. In this proposal we investigate the pathological consequences of peripheral inflammation on global cerebral ischemia, focusing on the relationship between lung inflammation, neutrophil priming and delayed CNS injury. These studies are based on our observation that expression of extracellular superoxide dismutase (EC-SOD) targeted to type II pneumocytes blunts neutrophil trafficking into the post-ischemic brain and confers marked neuroprotection. In this proposal we test the hypothesis that expression of EC-SOD within the lung inhibits IRI by reducing the production of damage associated molecular patterns (DAMPs) and levels of TLR4 activation required for endothelial and PMN activation. Successful demonstration that lung-brain coupling modulates delayed cerebral injury through effects on neutrophil priming may suggest new treatment strategies for patients presenting after cardiac arrest.